Journal of Saudi Chemical Society (2014) 18, 689–701

King Saud University

Journal of Saudi Chemical Society

www.ksu.edu.sawww.sciencedirect.com

ORIGINAL ARTICLE

Potassium phthalimide promoted green

multicomponent tandem synthesis of 2-amino-4H-

chromenes and 6-amino-4H-pyran-3-carboxylates

* Corresponding author. Tel./fax: +98 32 523 5431.

E-mail address: hkiyani@du.ac.ir (H. Kiyani).

Peer review under responsibility of King Saud University.

Production and hosting by Elsevier

1319-6103 ª 2014 King Saud University. Production and hosting by Elsevier B.V.

http://dx.doi.org/10.1016/j.jscs.2014.02.004

Open access under CC BY-NC-N

Open access under CC BY-NC-ND license.

Hamzeh Kiyani *, Fatemeh Ghorbani

School of Chemistry, Damghan University, 36715-364 Damghan, Iran

Received 24 December 2013; revised 30 January 2014; accepted 4 February 2014Available online 28 February 2014

KEYWORDS

4H-Chromene;

4H-Pyran-3-carboxylate;

Potassium phthalimide;

Multicomponent process

Abstract A one-pot efficient, green, practical, and environmentally friendly multicomponent syn-

thesis of 5-oxo-4-aryl-5,6,7,8-tetrahydro-4H-chromenes, ethyl-6-amino-4-aryl-5-cyano-2-methyl-

4H-pyran-3-carboxylates as well as 2-amino-4-aryl-7-hydroxy-4H-chromene-3-carbonitriles via tan-

dem the Knoevenagel-cyclocondensation has been described in the presence of a green, low-cost,

mild, efficient, and commercially available potassium phthalimide as the organocatalyst. This tech-

nique is a safe and ecofriendly approach to the synthesis of different 4H-chromens and 4H-pyrans

that offers many merits including short reaction times, high yields, straightforward work-up, and no

use of hazardous organic solvents.ª 2014 King Saud University. Production and hosting by Elsevier B.V.

D license.

1. Introduction

The heterocyclic scaffold containing 4H-chromene moiety ispresent in naturally occurring compounds and interestingpharmaceutically materials. 4H-Chromenes have attracted

great interest because they can exhibit a wide spectrum of bio-logical activities such as antimicrobial [18], antifungal [3], anti-bacterial [24], antioxidant [39], antileishmanial [29], anticancer

[1,30], and hypotensive [5]. Some of these compounds couldalso be used as inhibitors [40,15]. Some of 4H-chromenes

which display strong biological activity including antibacterial,

anticancer, and inhibitory are shown in Fig. 1.The multicomponent process (MCP) provides a powerful

method for the construction of a variety of chemicals including

pharmaceuticals, complex organic molecules, and biologicalactive compounds in a time- and cost-effective approach. Sinceits discovery over 160 years ago, the multicomponent processes

(MCPs) have been frequently applied in the synthesis of natu-ral products and other biological active molecules. In recentyears, significant consideration has been focused on MCPs be-cause of their valuable features such as high efficiency, mild

conditions, simplistic completion, and environment friendli-ness [37,36,35].

Due to the importance of 4H-chromene and 4H-pyran

derivatives, a variety of reactions have been developedfor the preparation of these compounds. One of the mostimportant reactions in this context is the multicomponent

tandem cyclocondensation reaction of an aldehyde, active

O

Ar

NH2

CNO

C: antibacterialand anticancer activity

O NH2

B: HA 14-1Bcl-2 inhibitor

CN

Br

O NH2

CN

OCH3OCH3

F: MX58151anticancer activity

Br

NH3C

CH3O NH2

CN

OCH3Br

E: EPC2407anticancer activity

H3CO

H2NNH2

O NH2

CN

OCH3

O

D: inhibitorof EAAT1

Ar: furan, pyrrole,thiophene

O NH2

CNBrO

O

O

O

O

O

A: anticancerand Bcl-2 inhibitor

O

O

Figure 1 Selected examples of chromene derivatives with biological, inhibitory, and pharmacological activity.

690 H. Kiyani, F. Ghorbani

methylene-containing material and enolizable CAH activatedacidic compound. Various types of homogeneous or heteroge-

neous catalysts have been applied to this transformation, suchas silica nanoparticles [4], MgO [24], ferric hydrogen sulfate[11], meglumine [13], [bmim]OH [12,21], lithium bromide [38],

ionic liquid choline chloride-urea [32], 4-(dimethylamino)pyri-dine (DMAP) [20], silica gel-supported polyphosphoric acid(PPA–SiO2) [7], Ba(OTf)2 [25], tetrabutyl ammonium bromide

(TBAB) [43], amino acids [41,14,6], potassium phthalimide-N-oxyl (POPINO) [10], nanosized ZnO [42], nanocrystallineMgO [33], NH4Al(SO4)2.12H2O (Alum) [28], hydrotalcite [17],tungstic acid functionalized SBA-15 [26], CoFe2O4 nanoparti-

cles [31] as well as DABCO [16]. Although these procedures

Ar H

ON

H2O, RefluxZ ==

PPI, 15 mol%

+

1

O

O

OO

Ar

NH2Z

O O

Z = CN, 6a-g

4

H2 O,Reflux

O

Ar

HO

PPI,15

mol%

HO

Z = CN,

N:K+

O

OPPI

Scheme 1 Preparation of 5-oxo-4-aryl-5,6,7,8-tetrahydro-4H-chrome

pyran-3-carboxylate derivatives (6a–g), and 2-amino-4-aryl-7-hydroxy

component tandem process.

are suitable for the synthesis of 4H-chromenes and 4H-pyrans,however, many of these approaches suffer from one or more

drawbacks, including prolonged reaction times, tedious work-up procedures, using expensive catalysts, and organic solventsas well as the requirement of special apparatus. Thus, develop-

ment of a catalytically efficient, rapid, simple, and green proce-dure for the synthesis of the organic molecules has beenattracted considerable attention in recent years. On the other

hand, implementation of chemical transformations in aquaticmedia is a fascinating field in the organic synthesis. Water isone of the best solvents due to its features such as beingenvironment friendly, cheap, safe, non-flammable, clean, green,

inexpensive, readily available, and risk-free. Also, use of water

C Z

O

O

O

Ar

NH2Z

OCN (2a)CO2Et (2b)

R1R2

3a, 3b

5a-w

H2O, RefluxPPI, 15 mol%

OH

NH2

Z

7

8a-j

O

O3a 3b

ne derivatives (5a–w), ethyl 6-amino-4-aryl-5-cyano-2-methyl-4H-

-4H-chromene-3-carbonitrile derivatives (8a–j) via one-pot, three-

Potassium phthalimide promoted green multicomponent tandem synthesis 691

not only diminishes the risk of organic solvents, but also im-proves the rate of many chemical reactions [27]. Interestingproperties of water allow its use in the organic transformations

as a useful solvent.Development of solid basic catalytic systems using the cost

effective, clean, environmentally benign and commercially

available catalysts has been a challenge in organic synthesis[8]. Potassium phthalimide (PPI) is a mild, green, inexpensive,commercially available, effective solid basic catalyst, and sta-

ble reagent. PPI has been reported to be a reagent and an effi-cient catalyst for some of organic transformations includingsynthesis of primary amines via Gabriel method [34], prepara-tion of cyanohydrin trimethylsilyl ethers [9], synthesis of iso-

xazol-5(4H)-ones [22] as well as Biginelli reaction [23]. Ourliterature survey revealed that there is no example on the useof PPI as the catalyst for the synthesis of 5-oxo-4-aryl-

5,6,7,8-tetrahydro-4H-chromenes, ethyl-6-amino-4-aryl-5-cya-no-2-methyl-4H-pyran-3-carboxylates, and 2-amino-4-aryl-7-hydroxy-4H-chromene-3-carbonitriles in water. This article

describes one-pot three-component tandem process involvingaldehydes (1), active nitrile-containing compounds (2a,b),and three 1,3-dicarbonyl components (3a, 3b, and 4) or resor-

cinol (7) using PPI as the catalyst. 5,5-Dimethylcyclohexane-1,3-dione (dimedone) (3a), 1,3-cyclohexanedione (3b), andethyl acetoacetate (4) as enolizable 1,3-dicabonyl substrateswere used in this tandem cyclocondensation reaction

(Scheme 1).

2. Experimental

2.1. General

All chemicals were purchased from Alfa Aesar and Aldrich aswell as were used without further purification, with the excep-tion of furan-2-carbaldehyde and benzaldehyde, which were

distilled before using. The following compounds were used asstarting materials. Benzaldehyde (Alfa Aesar, 98%), 4-nitro-benzaldehyde (Alfa Aesar, 99%), 3-nitrobenzaldehyde (Alfa

Aesar, 99%), 4-chlorobenzaldehyde (Alfa Aesar, 98%), 2,4-dichlorobenzaldehyde (Alfa Aesar, 98%), 4-methylbenzalde-hyde (Aldrich, 97%), 3-hydroxybenzaldehyde (Alfa Aesar,97%), 4-hydroxybenzaldehyde (Alfa Aesar, 98%), 4-methoxy-

benzaldehyde (Alfa Aesar, 98%), vanillin (Alfa Aesar, 99%),4-dimethylaminobenzaldehyde (Alfa Aesar 98%), 2-nitrobenz-aldehyde (Alfa Aesar 98%), furan-2-carboxaldehyde (Aldrich,

99%), thiophene-2-carbaldehyde (Alfa Aesar, 98%), malono-nitrile (Alfa Aesar, 99%), ethyl cyanoacetate (Alfa Aesar,98%). The following solvents were applied and were distilled

before using. Ethanol (Alfa Aesar, 96%), dichloromethane(Alfa Aesar, 98%), Acetonitrile (Alfa Aesar, 99.5%), petro-leum ether 40/60 (Alfa Aesar, ACS grade), 1,4-dioxane (Alfa

Aesar, 98%), chloroform (Alfa Aesar, 99.5), ethyl acetate(Alfa Aesar, 99.5). The products were characterized by com-parison of their physical data with those of known samplesor by their spectral data. Melting points were measured on a

Buchi 510 melting point apparatus and are uncorrected.NMR spectra were recorded at ambient temperature on aBRUKER AVANCE DRX-500 and 400 MHz using CDCl3or DMSO-d6 as the solvent. FT-IR spectra were recorded ona Perkin-Elmer RXI spectrometer. Elemental microanalyseswere performed on a Perkin-Elmer CHN-2400 analyzer. The

development of reactions was monitored by thin layer chroma-tography (TLC) analysis on Merck pre-coated silica gel 60 F254

aluminum sheets, visualized by UV light.

2.2. General procedure for the synthesis of chromene and pyran

derivatives (5a–w, 6a–g, 8a–j)

A reaction mixture of aryl aldehyde 1 (1 mmol), enolizablecompounds 3, 4, 7 (1 mmol), malononitrile or ethyl cyanoace-tate 2 (1 mmol), and potassium phthalimide (15 mol%) in dis-

tilled water (5 mL) was refluxed for 10–55 min. During thereflux, progress of the reaction mixture was monitored byTLC analysis. After completion of the reaction, the system

was cooled to room temperature and precipitated solid was fil-tered, washed with cold distilled water (4 mL), and air-dried toobtain the pure products. All the products were isolated purejust by washing with distilled water followed by recrystalliza-

tion from hot ethanol, if necessary. After removal of the waterfrom the filtrate solution, the catalyst is recovered and reusedfor the subsequent reaction. Spectral data for some com-

pounds are as follows:

2.2.1. 2-Amino-4-(furan-2-yl)-7,7-dimethyl-5-oxo-5,6,7,8-

tetrahydro-4H-chromene-3-carbonitrile (5m)

IR (KBr): m cm�1 3355, 3206 (NH2), 2942 (CArAH), 2205(C„N), 1682 (C‚O), 1650 (C‚C), 1195 (CAO); 1H NMR(400 MHz, DMSO-d6): d 0.99 (s, 3H, CH3), 1.04 (s, 3H,

CH3), 2.18 (m, 2H, CH2), 2.47 (m, 2H, CH2), 4.32 (s, 1H,CH), 6.06 (d, J = 3.9 Hz, 1H, ArAH), 6.32 (dd, J = 3.9,1.8 Hz, 1H, ArAH), 7.08 (s, 2H, NH2), 7.48 (d, J = 3.9 Hz,

1H, ArAH); 13C NMR (100 MHz, DMSO-d6): d 27.4, 29.4,31.3, 32.7, 50.8, 58.9, 113.9, 120.5, 124.7, 125.3, 127.8, 150.2,159.7, 163.4, 196.5. Anal. Calcd. for C16H16N2O3 (%): C,67.59; H, 5.67; N, 9.85. Found: C, 67.79; H, 5.64; N, 9.81.

2.2.2. 2-Amino-7,7-dimethyl-5-oxo-4-(thiophen-2-yl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (5n)

IR (KBr): m cm�1 3404, 3215 (NH2), 2975 (CArAH), 2204(C„N), 1680 (C‚O), 1660 (C‚C), 1198 (CAO); 1H NMR(400 MHz, DMSO-d6): d 0.99 (s, 3H, CH3), 1.05 (s, 3H,CH3), 2.31 (m, 2H, CH2), 2.49 (m, 2H, CH2), 4.34 (s, 1H,

CH), 6.33 (dd, J= 3.4 Hz, 1H, ArAH), 6.15 (d, J = 3.4 Hz,1H, ArAH), 6.05 (d, J = 3.4 Hz, 1H, ArAH), 7.08 (s, 2H,NH2);

13C NMR (100 MHz, DMSO-d6): 27.5, 29.6, 31.4,

32.6, 50.6, 58.4, 113.8, 121.1, 124.7, 125.7, 128.4, 151.4,159.7, 163.4, 196.5; Found: C, 64.15; H, 5.31; N, 9.43. Anal.Calcd. for C16H16N2O2S (%): C, 64.14; H, 5.33; N, 9.41.

2.2.3. 2-Amino-4-(4-(dimethylamino)phenyl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (5w)

IR (KBr): m cm�1 3325, 3275 (NH2), 2925 (CArAAH), 2196

(C„N), 1680 (C‚O), 1605, 1510 (C‚C), 1364 (CAN), 1192(CAO); 1H NMR (400 MHz, DMSO-d6): d 1.81–1.96 (m,2H, CH2), 2.18–2.30 (m, 2H, CH2), 2.52 (m, 2H, CH2), 4.06

(s, 1H, CH), 6.63 (d, J= 8.7 Hz, 2H, ArAH), 6.88 (s, 2H,NH2), 6.95 (d, J= 8.7 Hz, 2H, ArAH); 13C NMR(100 MHz, DMSO-d6): d 21.4, 27.3, 35.9, 38.2, 40.2, 59.2,114.9, 115.3, 118.6, 127.9, 136.4, 147.7, 159.3, 162.1, 197.6.

Anal. Calcd. for C18H19N3O2 (%): C, 69.88; H, 6.19; N,13.58 Found: C, 69.93; H, 6.22; N, 13.57.

692 H. Kiyani, F. Ghorbani

2.2.4. Ethyl 6-amino-5-cyano-2-methyl-4-(4-nitrophenyl)-4H-

pyran-3-carboxylate (6b)

IR (KBr): m cm�1 3398, 3331 (NH2), 3021 (CArAH), 2976, 2938(CaliphaticAH), 2192 (C„N), 1685 (C‚O), 1673, 1598 (C‚C),1524, 1340 (NO2), 1260, 1062 (CAO); 1H NMR (DMSO-d6): d1.12 (t, J = 7.1 Hz, 3H), 2.40 (s, 3H, CH3), 4.02–4.05 (m, 2H,OCH2A), 4.51 (s, 1H, CH), 6.21 (s, 2H, NH2), 7.44 (d,J= 8.4 Hz, 2H, ArAH), 8.16 (d, J = 8.4 Hz, 2H, ArAH).

2.2.5. 2-Amino-7-hydroxy-4-(4-nitrophenyl)-4H-chromene-3-carbonitrile (8c)

IR (KBr): m cm�1 3474 (OH), 3336 (NH2), 2980 (CArAH), 2188

(C„N), 1645, 1580 (C‚C), 1459, 1325 (NO2), 1150 (CAO); 1HNMR (400 MHz, DMSO-d6): d 4.88 (s, 1H, CH), 6.44 (d, 1H,J= 2.5 Hz, ArAH), 6.51 (dd, 1H, J= 8.4, 2.5 Hz, ArAH),

6.80 (d, 1H, J= 8.4 Hz, ArAH), 7.02 (s, 2H, NH2), 7.45 (d,2H, J = 8.8 Hz, ArAH), 8.21 (d, 2H, J= 8.8 Hz, ArAH),9.82 (s, 1H, OH); 13C NMR (100 MHz, DMSO-d6): d 55.4,79.6, 102.89, 112.7, 113.2, 118.7, 121.4, 125.4, 129.2, 130.6,

147.1, 154.3, 158.0, 161.2. Anal. Calcd. for C14H10N2O3 (%):C, 66.14; H, 3.96; N, 11.02. Found: C, 66.08; H, 4.02; N, 11.07.

2.2.6. 2-Amino-7-hydroxy-4-(4-hydroxyphenyl)-4H-chromene-3-carbonitrile (8f)

IR (KBr): m cm�1 3479 (OH), 3349 (NH2), 2980 (CArAH), 2184(C„N), 1645 (C‚C), 1587 (C‚C), 1459 (NO2), 1152 (CAO)

cm�1; 1H NMR (400 MHz, DMSO-d6): d 4.40 (s, 1H, CH),6.38 (d, 1H, J = 2.2 Hz, ArAH), 6.51 (dd, 1H, J = 2.2,

Table 1 Screening of reaction conditions.a

H

O

+ NC CN

O

OH3C

3a1f 2a

+

Entry Solvent Amount of catalyst (m

1 H2O –

2 H2O –

3 H2O 5

4 H2O 10

5 H2O 15

6 H2O 20

7 H2O 5

8 H2O 10

9c H2O 15

10 H2O 20

11 EtOH 15

12 MeCN 15

13 1,4-Dioxane 15

14 CH2Cl2 15

15 EtOAc 15

16 CHCl3 15

17 H2O/EtOH (1:1, V/V)d 15

a Reaction conditions: 4-methylbenzaldehyde (1 mmol), malononitrile (1b Isolated yields.c Optimized conditions shown in bold.d Ratio solvent is 1:1 (v/v).

8.4 Hz, ArAH), 6.69 (d, 2H, J= 8.4 Hz, ArAH), 6.95 (d,2H, J = 8.4 Hz, ArAH), 6.76–6.79 (m, 3H, NH2, ArAH),9.28 (s, 1H, OH), 9.83 (s, 1H, OH); 13C NMR (100 MHz

DMSO-d6): d 57.2, 102.6, 112.9, 114.7, 115.9, 121.3, 128.9,130.3, 137.3, 149.2, 156.7, 157.4, 160.9. Anal. Calcd. forC14H10N2O3 (%): C, 68.56; H, 4.32; N, 9.99. Found: C,

68.61; H, 4.35; N, 10.01.

2.2.7. 2-Amino-4-(furan-2-yl)-7-hydroxy-4H-chromene-3-

carbonitrile (8i)

IR (KBr): m cm�1 3478 (OH), 3419 (NH2), 2192 (C„N), 1651(C‚C), 1585 (C‚C); 1H NMR (400 MHz, DMSO-d6): d 4.75(s, 1H, CH), 6.12 (d, 1H, J = 2.0 Hz, ArAH), 6.32 (dd, 1H,

J= 2.0, 8.0 Hz, ArAH), 6.52 (d, 1H, J = 8.0 Hz, ArAH),6.95 (s, 2H, NH2), 7.27–7.50 (m, 3H, ArAH), 9.74 (s, 1H,OH); 13C NMR (100 MHz, DMSO-d6): d 53.8, 102.8, 106.8,

110.3, 112.4, 112.9, 116.3, 121.0, 130.4, 149.5, 151.4, 155.6,157.6, 161.3. Anal. Calcd. for C14H10N2O3 (%): C, 62.14; H,3.58; N, 13.59. Found: C, 62.12; H, 3.59; N, 13.57.

2.2.8. 2-Amino-3-cyano-7-hydroxy-4-(thiophenyl)-4H-chromene (8j)

IR (KBr): m cm�1 3458 (OH), 3420 (NH2), 2193 (C„N), 1651

(C‚C), 1587 (C‚C), 706 (CAS); 1H NMR (400 MHz,DMSO-d6): d 4.97 (s, 1H, CH), 6.16–6.18 (m, 1H, ArAH),6.38 (s, 2H, NH2), 6.50–6.54 (m, 1H, ArAH), 6.86–6.97 (m,3H, ArAH), 7.33–7.35 (m, 1H, ArAH), 9.74 (s, 1H, OH);13C NMR (100 MHz, DMSO-d6): d 56.5, 102.8, 106.8, 112.4,

O

O CH3

NH2CN

PPI

5f

conditions

ol%) Time (min) Temp. (�C) Yield (%)b

30 r.t. Trace

30 Reflux 25

30 r.t. 30

30 r.t. 34

30 r.t. 38

30 r.t. 40

25 Reflux 45

20 Reflux 80

20 Reflux 96

20 Reflux 95

25 Reflux 62

70 Reflux Trace

70 Reflux Trace

70 Reflux Trace

70 Reflux Trace

70 Reflux Trace

25 Reflux 75

mmol), 5,5-dimethylcyclohexane-1,3-dione (1 mmol), solvent (5 mL).

Table 2 Synthesis of 5-oxo-4-aryl-5,6,7,8-tetrahydro-4H-chromene derivatives (5a–w) and ethyl 6-amino-4-aryl-5-cyano-2-methyl-

4H-pyran-3-carboxylate derivatives (6a–g) via one-pot, three-component tandem reaction between 1,3-dicarbonyl compounds (3a, b,

and 4), aromatic aldehydes (1), and nitrile compounds (2a,b).a

Entry Aldehyde Active nitrile compound Product Time (min) Yield (%)b m.p. (�C) observed m.p. (�C) [Ref.]

1 CHO

1a

2a

O

NH2CN

O 5a

15 95 222–224 223–224 [12]

230–232 [38]

2 CHO

O2N1b

2a

O

NH2CN

NO2O 5b

12 96 183–185 179–180 [12]

180–181 [38]

3 CHOO2N

1c

2a

O

NH2CN

O

NO2

5c

10 97 209–210 208–209 [12]

4 CHO

Cl1d

2a

O

NH2CN

O Cl 5d

15 97 210–212 208–209 [12]

215–215 [38]

5

CHO

Cl

Cl

1e

2a

O

NH2CN

O Cl

Cl

5e

15 90 192–194 192–193 [12]

6 CHO

H3C1f

2a

O

NH2CN

O CH3 5f

20 96 216–218 217–218 [12]

224–225 [38]

7 CHO

HO1g

2a

O

NH2CN

O OH 5g

20 92 220–223 204–205 [12]

220–222 [38]

8 CHO

H3CO1h

2a

O

NH2CN

O OCH3 5h

20 94 198–199 198–200 [12]

202–203 [38]

(continued on next page)

Potassium phthalimide promoted green multicomponent tandem synthesis 693

Table 2 (continued)

Entry Aldehyde Active nitrile compound Product Time (min) Yield (%)b m.p. (�C) observed m.p. (�C) [Ref.]

9 CHO

HO

H3CO

1i

2a

O

NH2CN

O OH

OCH3

5i

25 98 239–242 240–242 [10]

10 CHOHO

1m

2a

O

NH2CN

O

OH

5j

20 91 226–227 224–226 [24]

11 CHO

NH3C

CH31k

2a

O

NH2CN

O N CH3CH3 5k

23 96 209–201 201–202 [12]

210–212 [10]

12 CHO

NO2 1n

2a

O

NH2CN

O

NO2

5l

10 95 220–222 223–224 [12]

13 CHOO

1j

2a

O

NH2CN

O

O

5m

25 94 225–227 225–226 [38]

14 CHOS

1l

2a

O

NH2CN

O

S

5n

25 95 217–220 216–218 [38]

15 CHO

1a

2b

O

NH2

O

O

O

5o

45 89 155–157 157–158 [38]

16 CHOO2N

1c

2b

O

NH2

O

O

ONO2

5p

40 90 153–155 154–156 [20]

694 H. Kiyani, F. Ghorbani

Table 2 (continued)

Entry Aldehyde Active nitrile compound Product Time (min) Yield (%)b m.p. (�C) observed m.p. (�C) [Ref.]

17 CHO

Cl1d

2b

O

NH2

O

O

O

Cl 5q

40 92 147–149 154–155 [38]

139–142 [20]

18 CHO

NCH3

H3C

1k

2b

O

NH2

O

O

O

NCH3

CH35r

45 92 156–157 155–157 [2]

19 CHO

Cl1d

2b

O

NH2

O Cl

O

O

5s

55 91 165–167 163–165 [20]

20 CHO

O2N1b

2a

O

NH2CN

O NO2 5t

10 95 222–224 221–222 [32]

21 CHO

Cl1d

2a

O

NH2CN

O Cl5u

10 97 218–220 228–229 [38]

203–205 [32]

22 CHO

H3C1f

2a

O

NH2CN

O CH3 5v

15 94 225–226 224–226 [38]

220–221 [32]

23 CHO

NH3C

CH31k

2a

O

NH2CN

O N CH3CH3 5w

15 94 223–225 223–224 [32]

24 CHO

1a

2a

O

O

NH2CN

O 6a

35 89 192–194 195–196 [24]

(continued on next page)

Potassium phthalimide promoted green multicomponent tandem synthesis 695

Table 2 (continued)

Entry Aldehyde Active nitrile compound Product Time (min) Yield (%)b m.p. (�C) observed m.p. (�C) [Ref.]

25 CHO

O2N1b

2a

O

O

NH2CN

NO2O 6b

25 92 180–182 176–178 [4]

180–183 [24]

26 CHOO2N

1c

2a

O

O

NH2CN

O

NO2

6c

25 92 172–173 171–173 [4]

27 CHO

Cl1d

2a

O

O

NH2CN

O Cl6d

30 88 172–173 172–174 [24]

28 CHO

H3C1f

2a

O

O

NH2CN

O CH3 6e

55 89 178–181 177–179 [21]

29 CHO

HO1g

2a

O

O

NH2CN

O OH 6f

35 90 174–177 175–177 [21]

30 CHO

H3CO1h

2a

O

O

NH2CN

O OCH3 6g

45 87 141–143 136–138 [4]

142–144 [24]

a All of the reactions were carried out using aromatic aldehydes (1 mmol), malononitrile (1 mmol) or ethyl cyanoacetate (1 mmol),

1,3-dicarbonyl compounds (1 mmol), water (5 mL), PPI (15 mol%), reflux.b Yields refer to those of pure isolated products.

696 H. Kiyani, F. Ghorbani

113.4, 121.6, 124.2, 126.8, 130.9, 149.6, 152.5, 157.4, 158.4,161.4. Anal. Calcd. for C14H10N2O2S (%): C, 62.21; H, 3.73;

N, 10.36. Found: C, 62.18; H, 3.70; N, 10.41.

3. Results and discussion

First, treatment of 4-methylbenzaldehyde (1f) with malononit-rile (2a) and 5,5-dimethylcyclohexane-1,3-dione (3a) in thepresence of catalytic amount of PPI in 5 mL of water afforded

almost quantitative yield of 2-amino-7,7-dimethyl-5-oxo-4-(p-tolyl)-5,6,7,8-tetrahyd ro-4H-chromene-3-carbonitrile (5f) un-der reflux conditions. This reaction was selected as a model

and optimized conditions were examined. The results are sum-marized in Table 1.

As evident from Table 1, in free-catalyst conditions, thereaction did not proceed at room temperature. Only a traceamount of 2-amino-7,7-dimethyl-5-oxo-4-(p-tolyl)-5,6,7,8-tet-

rahydro-4H-chromene-3-carbonitrile (5f) was achieved in thiscase (Table 1, entry 1). Also, it was revealed that the reactionwas rather slow and resulted in poor yield (25%) in the absence

of catalyst when the reaction was carried out in refluxing waterfor 30 min (Table 1, entry 2), which indicated that the catalystshould be necessary for this transformation. Although,increasing the reaction time did not improve the yield. The

yield also increased slightly by adding the amount of

Table 3 Synthesis of 2-amino-4-aryl-7-hydroxy-4H-chromene derivatives (8a–j) via one-pot, three-component tandem cycloconden-

sation reaction between resorcinol (7), aromatic aldehydes (1) and malononitrile (2a) catalyzed by PPI.a

Entry Aldehyde Product Time (min) Yield (%)b m.p. (�C) observed m.p. (�C) [Ref.]

1 CHO

1a

HO

O

NH2CN

8a

12 94 228–230 230–232 [12]

2 CHOO2N

1c

HO

O

NH2CN

NO2

8b

10 92 205–208 169–170 [19]

3 CHO

O2N 1b

HO

O

NH2CN

NO2 8c

10 96 209–211 210–212 [17]

4 CHO

Cl 1d

HO

O

NH2CN

Cl 8d

10 96 162–164 162–163 [12]

5 CHO

H3C 1fO

NH2CN

CH3HO 8e

15 92 185–187 187 [11]

6 CHO

HO 1g

HO

O

NH2CN

OH 8f

25 98 252–254 252–254 [10]

7 CHO

H3CO 1h

HO

O

NH2CN

OCH3 8g

15 96 110–112 112–113 [20]

8 CHO

NH3C

CH3 1kHO

O

NH2CN

N CH3CH3 8h

25 95 189–191 190–192 [10]

(continued on next page)

Potassium phthalimide promoted green multicomponent tandem synthesis 697

Table 3 (continued)

Entry Aldehyde Product Time (min) Yield (%)b m.p. (�C) observed m.p. (�C) [Ref.]

9 CHO

O 1j

HO

O

NH2CN

O

8i

25 92 186–189 189–191 [19]

10 CHO

S 1l

HO

O

NH2CN

S

8j

20 97 205–206 204–205 [19]

a All of the reactions were carried out using aromatic aldehydes (1 mmol), malononitrile (1 mmol), resorcinol (1 mmol), water (5 mL), PPI

(15 mol%), reflux.b Yields refer to those of pure isolated products.

698 H. Kiyani, F. Ghorbani

potassium phthalimide (PPI) to the reaction mixture at roomtemperature (Table 1, entry 3). The reaction was also evaluated

in the presence of different amounts of the catalyst. It wasfound that using 15 mol% of PPI in refluxing water was suffi-cient for the reaction to completion after 20 min. Increasing

the loading amount of the catalyst (20 mol%) did not consid-erably affect the yield and conversion time (Table 1, entry 10).The model reaction in refluxing MeCN, 1,4-dioxane, CH2Cl2,EtOAc, and CHCl3 in the presence of 15 mol% of catalystgave trace amounts of product even after 70 min (Table 1, en-tries 12–16). The yields were moderate in the case of EtOH(62%, Table 1, entry 11) and a mixture solvent of EtOH–

H2O (1:1, V/V) (75%, Table 1, entry 17) after 25 min at reflux.Implementation of the reaction in water in the presence of15 mol% of PPI gave the yield of 96% after 20 min at reflux

(Table 1, entry 9). It is probable that the high yields obtainedin water relative to the other organic solvents investigated aredue to the high solubility of PPI in water. Hence, the 15 mol%

of catalyst loading and refluxing in water was considered to bethe most conditions for this type reaction.

Based on the results presented in Table 2 (entries 1–23), itcan be seen that the PPI-catalyzed three-component tandem

cyclocondensation reaction worked well for the synthesis ofthe target compounds under the optimized reaction conditions.Various types of substituted aromatic aldehydes were used

including electron-donating and electron-withdrawing substit-uents. Corresponding products (5a–w) were obtained in shortreaction times and high to excellent yields. The results show

that the electronic nature of the substituent on the aromaticmoiety has little effect on the yields. In addition, for aromaticaldehydes 1e and 1n that have steric hindrance, products (5e

and 5l) were obtained with high yields (Table 2, entries 5and 12). Hence, steric factors show no remarkable effect onthe rate and the yield of this reaction. Furthermore, p-excessiveheterocyclic aldehydes, such as furan-2-carbaldehyde (1j) and

thiophene-2-carbaldehyde (1l) were also tested and 5m–n wereobtained in excellent yields (Table 2, entries 13 and 14). In allcases, the reaction was clean, and no chromatographic separa-

tion was performed because no impurities were observed. Also,the reaction with ethyl cyanoacetate (2b) proceeded smoothly.

Nonetheless, the reaction rate of ethyl cyanoacetate (2b) withcyclic 1,3-dicarbonyl compounds (3a,b) was slower than that

of malononitrile (2a), which is possibly owing to the lowerreactivity of the cyanoacetates or may be ascribed to the com-petency of the cyanide group in stabilizing the reaction inter-

mediates compared to the ester group [27,19]. Then, weextended our studies by using ethyl acetoacetate (4) as theenolizable starting material instead of 5-substituted-1,3-cyclo-

hexanedione (3a,b). It was found that the aforementionedcompound also easily reacted with substituted benzaldehydesand malononitrile in high yields (Table 2, entries 24–30). Theethyl 6-amino-5-cyano-2-methyl-4-aryl-4H-pyran-3-carboxyl-

ate derivatives (6a–g) were formed following the optimal pro-cedure for the compounds 5a–w. Also in this case, theexperimental technique is simple and the reaction went to com-

pletion at reflux conditions, within 25–55 min. Differentlysubstituted benzaldehydes depending on their reactivity readilyunderwent the tandem cyclocondensation reaction, which pro-

ceeded with excellent yields. Reactions of substituted benzalde-hydes with electron-withdrawing groups such as chloro andnitro, proceeded at faster rates than those with electron-donat-ing groups such as methoxy, hydroxy, and methyl.

The capability of PPI catalyst was also explored for the tan-dem cyclocondensation reaction of aryl aldehydes (1) includingthose containing electron-donating and electron-withdrawing

groups such as AOCH3, ACH3, AOH, AN(CH3)2, ANO2,and ACl as well as aromatic heterocyclic aldehydes for in-stance furan-2-carbaldehyde (1j) and thiophen-2-carbaldehyde

(1l) with malononitrile (2a) and resorcinol (7), as an activatedphenol, in refluxing water (Table 3). In this reaction, the corre-sponding 2-amino-4-aryl-7-hydroxy-4H-chromene derivatives

(8a–j) were obtained in 92–98% yield when 15 mol% of PPIwas employed. Aromatic aldehydes containing electron-with-drawing and electron-donating substituents at the phenyl ringand hetero-aryl aldehydes are active under the optimized reac-

tion conditions. According to the data indicated in Table 3,due to steric crowded hydroxyl groups in resorcinol (7), thereaction at C-4 position is implemented.

The mechanistic formulation for the formation of finalproducts (5, 6 and 8) is represented in Scheme 2. Elimination

Potassium phthalimide promoted green multicomponent tandem synthesis 699

of the acidic hydrogen from active nitrile-containing com-pounds (2a,b) by PPI, leads to the formation of intermediatenitrile anion 9. The arylidene nitrile intermediates (Knoevena-

gel products) (13) were formed via the Knoevenagel condensa-tion reaction of aldehydes (1) with intermediate nitrile anion 9.Then, the Michael-type addition of the enolizable compounds

to the Knoevenagel intermediates 13 gives rise to the in situformation of the Michael adducts 14, which proceeds throughintramolecular nucleophilic cyclization (Thorpe–Ziegler type

reaction) and tautomerization to afford the final compounds.

Table 4 Comparison of the results for the synthesis of 2-amino-

carbonitrile derivatives with reported protocols for compound 5h.

H3CO

H

O

+ NC CN +

O

1h 2a 3a

Catalyst/conditions Catalyst amount (m

SiO2 NPs/r.t./EtOH 5

MgO/grinding/ r.t. 50

[bmim]OH/H2O/100 �C 25

LiBr/H2O/reflux 10

POPINO/H2O/reflux 5

NH4Al(SO4)2Æ12H2O (Alum)/EtOH/80 �C 20

PPA-SiO2/H2O/reflux 0.1 g

Glycine/H2O/sonication 15

PPI/H2O/reflux 15

NC Z

H

N

O

O

K

NC Z

HN

O

O

+ArH

O

-2a-b 9

OHO N

O

O

K

N

O

O O

ArZ

NH2+

PPI

PPI

5, 6, 8

1

3a, 3b, 4, 7 12

Knoevconden

TautomerizationK

Scheme 2 The mechanistic formulation for the formation of 2-amino

caboxylates (6).

To compare the effectiveness of PPI with other catalysts inthe preparation of 2-amino-4-(4-methoxyphenyl)-7,7-di-methyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile

(5h), results of the reaction of 4-methoxybenzaldehyde (1h),malononitrile (2a), and 5,5-dimethylcyclohexane-1,3-dione(3a) are presented in Table 4. As can be seen in Table 4, PPI

is comparable to the previously reported methods in terms ofreaction times and yields.

The recyclability of the catalyst was tested in the model

reaction as well. After completion of the reaction, as indicated

4-(4-aryl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-

O

O

O

CNNH2

OCH35h

Catalyst

Conditions

ol%) Time (min) Yield (%) Reference

25 98 [4]

15 89 [24]

20 87 [12]

15 92 [38]

25 89 [10]

130 90 [28]

14 84 [7]

18 91 [6]

20 94 Current work

NC Z

Ar O

HN

O

O

N

O

O

-

NC Z

Ar OHH

- H2O

OCN

Z

O

Ar

C

Z

N

H

K

O

Ar

C

Z

NH

H

HN

O

O

N

O

O

-

+

10 11

13Knoevenagelintermediats

14Michael adducts

15

Ar

Michael-typereaction

enagelsation

Thorpe-Ziegler type

reaction (O-attack)

-4H-chromene-3-carbonitriles (5 and 8) and 6-amino-4H-pyran-3-

Table 5 Results obtained using recycled PPI.a

No. of cycles 1 2 3 4 5

Time (min) 20 20 20 25 25

Isolated yields (%) 96 92 90 88 85

a Reaction was carried out using 4-methylbenzaldehyde (1 mmol),

malononitrile (1 mmol), 5,5-dimethylcyclohexane-1,3-dione

(1 mmol), catalyst, water (5 mL), reflux.

700 H. Kiyani, F. Ghorbani

by TLC analysis, the solid product was filtered and the aque-ous filtrate solution was evaporated under reduced pressure.

The achieved solid was washed with a small amount of water,dried at 60 �C, and reused for the same reaction again. It wasobserved that the PPI could be reused and recycled for five

times, 96%, 92%, 90%, 88%, and 85% isolated yield(Table 5).

4. Conclusions

In summary, we have developed an efficient PPI-catalyzedone-pot three-component methodology for the synthesis of

a variety of pharmaceutical interesting functionalized 4H-chromene and 4H-pyran derivatives in high to excellentyields. This approach is very simple from the experimentalpoint of view and would permit easy access to large families

of 4H-chromenes and 4H-pyrans. Clean, avoiding the use ofhazardous organic solvents, absence of tedious separationtechniques, minimized amount of waste for each organic

transformation, reasonable reaction times, aqueous condi-tions, efficiency, green, reusability and economic availabilityof the organocatalyst are the other noticeable features of this

procedure.

Acknowledgment

The authors are grateful to the Research Council of DamghanUniversity for the financial support of this research work.

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